Clinical and molecular characteristics of a family with familial hypercholesterolemia with LDLRAP1 and ABCG8 gene abnormality / 中华检验医学杂志

Objective:To study the clinical and molecular characteristics of a family with familial hypercholesterolemia (FH) with LDLRAP1 and ABCG8 gene abnormality.Methods:In September 2020, one case of FH was included in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; peripheral venous blood samples of members of the family were collected to detect serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) indicators; use high-performance liquid chromatography to detect serum stigmasterol and sitosterol content; perform second-generation gene sequencing to detect gene mutations in probands and family members; use Pymol software to detect gene mutations point for pathogenicity analysis, and use Uniprot Modelling software to perform protein structure modeling.Results:The patient presented with anemia, multiple xanthomas and early-onset acute coronary syndrome. The coronary angiography showed severe coronary artery lesions; abdominal ultrasound showed splenomegaly; blood smear showed shaped erythrocytes and large platelets. The level of serum TC, LDL-C, stigmasterol and sitosterol was 8.54 mmol/L (2.3-5.7 mmol/L), 4.84 mmol/L (range of normal value 1.3-4.3 mmol/L), 44 μmol/L (1.0-10 μmol/L), 28 μmol/L (1.0-15 μmol/L), respectively; LDLRAP1 gene mutation was found: exon4 c.415C>T:p.Q139X; the truncated protein formed by this homozygous mutation lost multiple stable protein structure regions, which can not have a normal function. At the same time, ABCG8 gene mutations were also found: exon13 c.1895T>C (p.V632A) and exon8 c.1199C>A:p.T400K . Two cases of family members had a mild increase in HDL-C (Ⅱ5: 2.33 mmol/L, Ⅱ6∶2.96 mmol/L), 3 cases carrying the ABCG8 gene mutations had a slight increase in stigmasterol (Ⅱ8: 23 μmol/L, Ⅱ7: 24 μmol/L, Ⅰ2: 18 μmol/L) and sitosterol (Ⅱ8: 41 μmol/L, Ⅱ7: 33 μmol/L, Ⅰ2: 45 μmol/L), suggesting that its association with the concentration of plant sterols. Conclusions:FH patients with LDLRAP1 and ABCG8 gene abnormalities may have abnormal plant sterol concentrations, and their clinical manifestations are more complicated. Therefore, family history, LDL-C, plant sterol levels, and genetic test results should be considered comprehensively.

Efficacy of Ezetimibe tablets in the treatment of sitosterolemia with thrombocytopenia / 中华实用儿科临床杂志

The clinical features and genetic variants of the patient with sitosterolemia who was referred to Shanghai Children′s Medical Center, Shanghai Jiaotong University School of Medicine from June 2019 to January 2020 were retrospectively analyzed.The patient was treated with Ezetimibe tablets combined with diet control, and the follow-up was performed regularly.Besides, a relevant literature review was conducted.A 7-year and 5-month-old boy was referred to the hospital for " repeated thrombocytopenia for 7 months" with normal serum cholesterol.The whole exome sequencing showed that compound heterozygous mutations (p.Arg446*, p.Gln251*) in ABCG5 gene were inherited from their parents respectively.Hence, he was diagnosed with sitosterolemia.After 29 days of treatment with Ezetimibe tablets combined with diet control, the patient′s platelets returned to normal values without obvious adverse reactions related to drugs.Children with sitosterolemia may present with rare thrombocytopenia, and the therapeutic effects of Ezetimibe tablets combined with diet control are favorable.

Diagnosis and management of sitosterolemia / 国际儿科学杂志

Sitosterolemia is a rare autosomal recessive disorder,which is caused by increased intestinal absorption and decreased biliary excretion of plant sterols resulting from heterozygous mutations in either ABCG5 or ABCG8 gene.Sitosterolemia is characterized by increased serum plant sterol levels,hypercholesterolemia,xanthomas,accelerated atherosclerosis,and some patients have hematologic manifestations such as stomatocytic hemolysis,macrothrombocytopenia,etc.Early diagnosis can be made by serum plant sterol detection by gas chromatography mass spectrometry or liquid chromatography mass spectrometry,or ABCG5 and ABCG8 gene sequencing.The mainstay of therapy includes dietary restriction of both cholesterol and plant sterols,and the sterol absorption inhibitor or bile acid sequestrants.This article reviewed recent publication of sitosterolemia at home and abroad.

Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management

Sitosterolemia is an autosomal recessive disorder characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, severe hypercholesterolemia have been reported in patients with sitosterolemia, especially in children. Sitosterolemia is caused by increased intestinal absorption and decreased biliary excretion of sterols resulting from biallelic mutations in either ABCG5 or ABCG8, which encode the sterol efflux transporter ABCG5 and ABCG8. Patients with sitosterolemia show extreme phenotypic heterogeneity, ranging from almost asymptomatic individuals to those with severe hypercholesterolemia leading to accelerated atherosclerosis and premature cardiac death. Hematologic manifestations include hemolytic anemia with stomatocytosis, macrothrombocytopenia, splenomegaly, and abnormal bleeding. The mainstay of therapy includes dietary restriction of both cholesterol and plant sterols and the sterol absorption inhibitor, ezetimibe. Foods rich in plant sterols include vegetable oils, wheat germs, nuts, seeds, avocado, shortening, margarine and chocolate. Hypercholesterolemia in patients with sitosterolemia is dramatically responsive to low cholesterol diet and bile acid sequestrants. Plant sterol assay should be performed in patients with normocholesterolemic xanthomas, hypercholesterolemia with unexpectedly good response to dietary modifications or to cholesterol absorption inhibitors, or hypercholesterolemia with poor response to statins, or those with unexplained hemolytic anemia and macrothrombocytopenia. Because prognosis can be improved by proper management, it is important to find these patients out and diagnose correctly. This review article aimed to summarize recent publications on sitosterolemia, and to suggest clinical indications for plant sterol assay.